The contribution of cholesterol supersaturation of bile to the pathogenesis of gallstone disease is well defined. Less clear is the etiologic role of other factors such as gallbladder mechanical function. We plan on testing the hypothesis that sphincterotomy, i.e., the disruption of the musculature constituting the sphincter of Oddi, might alter gallbladder filling/emptying dynamics and thereby affect gallstone formation. Preliminary investigations have been carried out using adult, male prairie dogs which consistently make gallstones when fed a high cholesterol diet. These studies indicate that sphincterotomy alters gallbladder storage function, alleviates diet-induced gallbladder stasis, and markedly inhibits gallstone formation despite the continued presence of supersaturated bile. The studies outlined in this proposed are designed to further define the interrelationship between sphincter dynamics, bile flow, and gallbladder motor function and the possible role of the gallbladder in the pathogenesis of cholesterol cholelithiasis. Our plan is to pursue these studies in dogs in three phases: 1) during a presphincterotomy control period, 2) postsphincterotomy, and 3) after truncal vagotomy (in an effort to reverse the effects of sphincterotomy). During each phase of the experiment several parameters will be evaluated including: a) direct measurement of gallbladder volume at laparotomy, b) the degree of gallbladder filling determined by the actual mapping of bile flow with intravenously infused ICG, c) gallbladder emptying efficiency by measuring the output of BSP (loaded into the gallbladder by intravenous infusion 12 hours prior to study) in response to hormonal stimulation, d) biliary lipid composition, and 3) biliary ductal pressures. The effect of sphincterotomy on gallstones already present in the gallbladder will also be assessed. Human studies are also described during which the above parameters will be studied before and after a medically indicated therapeutic sphincterotomy in patients with papillary stenosis. The ultimate outcome of this endeavor could well advance our understanding of the pathophysiology of gallstone formation and lead to the development of new therapeutic modalities for the treatment of gallstone disease.